symposium review: going native: voltage-gated potassium channels controlling neuronal excitability

J Physiol 588.17 (2010) pp 3187–3200 3187

SYMPOS IUM REVIEW

Going native: voltage-gated potassium channelscontrolling neuronal excitability

Jamie Johnston2, Ian D. Forsythe1 and Conny Kopp-Scheinpflug1

1MRC Toxicology Unit, Hodgkin Bldg, University of Leicester, Leicester LE1 9HN, UK2Neurobiology Group, MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK

In this review we take a physiological perspective on the role of voltage-gated potassium channelsin an identified neuron in the auditory brainstem. The large number of KCN genes for potassiumchannel subunits and the heterogeneity of the subunit combination into K+ channels makeidentification of native conductances especially difficult. We provide a general pharmacologicaland biophysical profile to help identify the common voltage-gated K+ channel families ina neuron. Then we consider the physiological role of each of these conductances from theperspective of the principal neuron in the medial nucleus of the trapezoid body (MNTB). TheMNTB is an inverting relay, converting excitation generated by sound from one cochlea intoinhibition of brainstem nuclei on the opposite side of the brain; this information is crucialfor binaural comparisons and sound localization. The important features of MNTB actionpotential (AP) firing are inferred from its inhibitory projections to four key target nucleiinvolved in sound localization (which is the foundation of auditory scene analysis in higherbrain centres). These are: the medial superior olive (MSO), the lateral superior olive (LSO),the superior paraolivary nucleus (SPN) and the nuclei of the lateral lemniscus (NLL). The Kvfamilies represented in the MNTB each have a distinct role: Kv1 raises AP firing threshold; Kv2influences AP repolarization and hyperpolarizes the inter-AP membrane potential during highfrequency firing; and Kv3 accelerates AP repolarization. These actions are considered in termsof fidelity of transmission, AP duration, firing rates and temporal jitter. An emerging themeis activity-dependent phosphorylation of Kv channel activity and suggests that intracellularsignalling has a dynamic role in refining neuronal excitability and homeostasis.

(Received 22 April 2010; accepted after revision 28 May 2010; first published online 2 June 2010)Corresponding author I. D. Forsythe: MRC Toxicology Unit, University of Leicester, Leicester, LE1 9HN, UK.Email: [email protected]

Abbreviations AIS, axon initial segment; AP, action potential; CF, characteristic frequency; DTx-I, Dendrotoxin-I;ERG, ether-a-go-go related gene K+ channel family; HVA, high-voltage activated; HCN, hyperpolarization-activated,non-specific cation channels mediating IH.; IID, interaural intensity difference; ITD, interaural time difference; Kv1.1 etc,Voltage-gated potassium channel family 1, member 1; LSO, lateral superior olive; LVA, low-voltage activated; MNTB,medial nucleus of the trapezoid body; MSO, medial superior olive; NLL, nuclei of the lateral lemniscus; SPN, superiorparaolivary nucleus; TEA, tetraethylammonium; VCN, ventral cochlear nucleus.

Jamie Johnston did his PhD with Ian Forsythe and a postdoctoral fellowship with KerryDelaney in British Columbia before returning to Leon Lagnardo’s laboratory in the MRCLaboratory of Molecular Biology. Ian Forsythe started in Leicester as a postdoc in PeterStanfield’s Ion Channel Group in 1988; following a Wellcome Trust Senior ResearchFellowship, he became Professor of Neuroscience in the Department of Cell Physiologyand Pharmacology in 2000 and in 2005 moved from the University of Leicester to the MRCToxicology Unit. Conny Kopp-Scheinpflug did her PhD in Leipzig with Rudolf Rubsamenand a postdoctoral fellowship with Bruce Tempel in Seattle, thereafter returning to Leipzigfor her Habilitation; she joined Ian Forsythe’s group in 2009. We share a common interestin understanding synaptic transmission and integration in the central auditory pathwayand in the control of neuronal excitability by voltage-gated potassium channels. Ourresearch methods span from in vivo single-unit recording and multi-photon imaging toin vitro whole-cell patch recording, voltage-clamp and immunohistochemistry.

This review was presented at The Peter Stanfield Festschrift, which took place at the Warwick Medical School, University of Warwick, Coventry, UKon 12 April 2010.

C© 2010 The Authors. Journal compilation C© 2010 The Physiological Society DOI: 10.1113/jphysiol.2010.191973

3188 J. Johnston and others J Physiol 588.17

Introduction: defining potassium currents in nativeneurons

When delayed rectifying potassium currents were shownto be the basis of action potential (AP) repolarization(Hodgkin & Huxley, 1952), it was never envisaged thatthere would be such a huge number of genes dedicated tothis function: there are around 40 subunit genes dividedinto around 12 families (Coetzee et al. 1999; Gutman et al.2003). Generally a functional channel requires associationof four α subunits, usually from within the same familyand may include β subunits or other accessory proteins.K+ channels share a highly conserved pore structure,providing high selectivity for K+ ion permeation (Doyleet al. 1998; Yellen, 2002; MacKinnon, 2003). Elaborationof this structure forms the basis for the rich diversity ofpotassium channel properties and functions, but thesesubtle differences make it difficult to confidently assignspecific roles to identified subunits in most neurons.

Knowledge of K+ channels is dominated by studiesof recombinant homomeric channels in cell lines, butthis gives limited understanding of heteromeric channelsin native neurons. First one must obtain good qualityvoltage-clamp data, but the extensive dendritic treesof many neurons make space-clamp imperfect, whilethe magnitude of outward currents means that thevoltage-clamp error (generated by the current passingacross the pipette series resistance in whole-cell recording)is very large, even with series resistance compensationcircuitry. These and other issues have been well consideredelsewhere (Williams & Mitchell, 2008; Clay, 2009).

Resting membrane potentials are generally set byexpression of inward rectifiers mediated by the Kir channelfamily and by the leak channels, ‘outward rectifiers’mediated by the tandem-pore (K2p) K+ channels (seereview from A. Mathie in this issue). These channelsare not gated, but show rectification either through poreblock (Kir) or arising from the highly asymmetric internaland external [K+]. Kv channels activating around restingpotentials, such as Kv1 and hyperpolarization-activatednon-specific cation channels, IH (HCN are structurallyrelated to Kv) will also influence the resting potential andsynaptic integration (Garden et al. 2008; Oertel et al. 2008;Hassfurth et al. 2009).

Basic gating/kinetic properties of the K+ channelfamilies

Within the limitations of voltage-clamp in the whole-cellpatch configuration, we can obtain biophysical parametersof the currents which are characteristic of particularfamilies (Gutman et al. 2003). The dominant neuronaldelayed rectifiers in mammals are from the corevoltage-gated channel families: Kv1–Kv4. Each familycontains multiple genes specifying subunits which are

homologous to the single prototypical genes expressedin Drosophila: shaker, shab, shaw and shal, respectively.The biophysical properties of native ion channels differin rather subtle ways and given their heterogeneouscomposition, precise identification is possible only underspecial circumstances. Family traits are recognizable, soit seems reasonable to propose that Kv families arespecialized for particular functions, but there is necessarilyconsiderable overlap and interaction. Kv1, Kv4 and Kv7channels are low-voltage-activated (LVA; Fig. 1) openingon small depolarizations from around resting potentials,and so are a powerful means of regulating AP numberon depolarization or during an EPSP (Brew et al. 2003,2007; Coetzee et al. 1999; Brown & Passmore, 2009). Kv4channels generate the classic A-current, a transient K+

current, which requires prior hyperpolarization to removesteady-state inactivation before it can activate (Maffie& Rudy, 2008). Kv3 currents are high voltage activated(HVA; Fig. 1) requiring voltages achieved only duringAPs, and their fast kinetics mean that they contributeto AP duration and fast firing. Kv2 are also HVA, buthave slower kinetics, and their association with accessoryproteins (gene families: Kv5, Kv6, Kv8 and Kv9) makes theirproperties difficult to match with recombinant counter-parts.

The IUPHAR web site (Gutman et al. 2003) providesbroad introductory information on ion channel propertiesand their pharmacology. Many pharmacological agentsare not so specific that they can be used as thesole means of identification for potassium channels.Tetraethylammonium (TEA) will block many Kv channelsat high concentrations (Armstrong & Binstock, 1965;Stanfield, 1983) but at low concentrations it is relativelyeffective at blocking Kv3 channels (Fig. 2). The approachwe have taken is to build a series of simple pharmacologicaltests, which when combined with biophysical data canindicate the Kv family of a native neuronal conductance,with additional immuno-histochemical, PCR and/ortransgenic data providing further confirmation. The basicpharmacological protocol is presented in Fig. 2. At presentit has only been applied to auditory brainstem neurons,but it should be applicable to other brain areas. Certainantagonists such as the dendrotoxins are highly specificand provide clear evidence for the channel family (Harvey& Robertson, 2004); in a few cases, subunit-specific toxinscan be employed to give even more precise data (e.g. Kv1.1block by dendrotoxin-K; see Dodson et al. 2002).

The crucial physiological insights to understanding thebiophysical roles of different potassium channel familiesmay be realized by focusing studies on a specific identifiedneuron, which participates in a particular computationalprocess. Our interest in the control of excitability in themedial nucleus of the trapezoid body (MNTB) and itsgiant synapse, the calyx of Held (Dodson & Forsythe, 2004;Schneggenburger & Forsythe, 2006), provides an ideal

C© 2010 The Authors. Journal compilation C© 2010 The Physiological Society

J Physiol 588.17 K+ channels and auditory processing 3189

Figure 1. Functional classification of voltage-gated potassiumcurrentsA, voltage clamp permits the biophysical properties of the nativechannel types to be distinguished in terms of voltage-dependentactivation kinetics. Generalization of these properties is expressed hereas a matrix of low-voltage-activated (LVA) channels such as Kv1, Kv4and Kv7, and high-voltage-activated channels (HVA) Kv3 and Kv2. Kv4channels (mediating A-type currents) are inactivated at rest and sorequire prior hyperpolarization before they will activate. The spectrumof their channel kinetics further divides these groups into those thatactivate rapidly (Kv1, Kv4 and Kv3) and more slowly (Kv7 and Kv2). B,under conventional voltage recording (current clamp) the Kv channelkinetics mean that each channel activates over a characteristic part ofthe overall AP waveform as represented by the coloured bars/arrows:LVA channels open on depolarization from resting potentials (−70 mV)to around −40 to −30 mV, so influencing the threshold for AP firing.HVA channels require further depolarization, approaching 0 mV, whichis only achieved during APs, so these channels contribute torepolarization. Kv1 channels would turn on with small depolarizations,while Kv3 would be delayed until further depolarization. Kv2 wouldbe even later due to its slow kinetics, but its activity

preparation to explore native K+ channels in the contextof auditory processing. This nucleus has the advantages ofsimple morphology (the calyx of Held synapse forms onthe soma of a neuron with few dendrites) and predictableneuronal properties. The MNTB is an ideal site at which toaddress these integrative questions; but first let us brieflyconsider the function of the MNTB in auditory processing:what is it doing, where does it project, how is it adapted tothese postulated computational roles?

What is the MNTB doing?

Three elementary properties of sound are encoded into APtrains of the 8th nerve by the cochleae: frequency (tone),intensity (volume) and time (onset, phase). The frequencyof sound is transformed into a place code (tonotopy) bythe resonance of the basilar membrane, so that inner haircells close to the oval window (at the base of the cochlea)respond to high frequencies and as the resonance evolveswith distance along the basilar membrane, increasinglylow frequencies are represented toward the apex. Thistonotopic map is preserved and adapted in the centralauditory projection (Kandler et al. 2009) with each neuronhaving a characteristic frequency (CF) to which it fires withthe lowest threshold. For a given frequency (and withinneuronal populations) sound intensity is encoded by APfiring rate; usually with higher rates representing loudersounds. Finally, timing is important for localization of asound source, which requires integration of AP encodedsounds from two cochleae for computation of interauraltiming and intensity differences (Oertel, 1999; Trussell,1999). This computation first occurs in two distinct nucleiof the brainstem superior olivary complex, each of whichreceives inhibitory inputs from the MNTB.

The MNTB is an inverting relay, providing an ipsilateralglycinergic inhibition from contralateral excitation (i.e.from the sound received on the opposite side of the head).This input arrives from the bushy cells of the ventralcochlear nucleus (VCN) via the calyx of Held (Fig. 3, inset).Each MNTB projects to four auditory nuclei: the medialsuperior olive (MSO; Smith et al. 2000; for review see

extended to longer time points as it is slow to turn off. Althoughthis diagram is a vast oversimplification, it gives a framework inwhich to identify native potassium currents and their different rolesin determining neuronal excitability. Note that little emphasis is placedon inactivation, since this is so dependent on the precise subunitcomposition of the channel, but it is nonetheless important; Kv4channels invariably inactivate, with a time course which is highlydependent on subunit and accessory proteins. Inactivation (for reviewssee Robertson, 1997; Aldrich, 2001) plays an important role in reducingthe Kv contribution during sustained activation, for instance increasingAP duration during repetitive firing.



Grothe, 2003; Fig. 3B), the lateral superior olive (LSO; forreview see Tollin, 2003; Kandler et al. 2009; Fig. 3C), thesuperior paraolivary nucleus (SPN; Banks & Smith, 1992;Kulesza et al. 2007; Fig. 3D) and the nuclei of the laterallemniscus (NLL; Glendenning et al. 1981; Yavuzoglu et al.2010; Fig. 3E). We will briefly review the function ofeach nucleus, highlighting the role of the MNTB at eachstage.

(1) The MSO projection. Low-frequency sounds(<2 kHz) with a wavelength long enough to give twodistinct phases at opposite ears within one sound cycleare localized by interaural time differences (ITDs) of

the sound stimulus. There are two theories for ITDprocessing based on coincidence detection: first, via‘hard-wired delay lines’ (Jeffress, 1948; for discussion seeJoris & Yin, 2007) and second via ‘virtual delay lines’introduced by either tonic inhibition (Zhou et al. 2005) orwell-timed inhibition from the MNTB (Pecka et al. 2008).Both theories require temporal and spatial summationof phase-locked inputs, in which summation of EPSPsfrom left and right ears are refined by voltage-gatedconductances, such as Kv1 (Mathews et al. 2010).MNTB-mediated inhibition shifts the slope (rather thanthe peak) of the ITD functions into the physiologicallyrelevant range, so that near linear changes in firing rate

Figure 2. Pharmacological profile for native delayed rectifier Kv familiesSince native channels are often heteromers, precise biophysical and pharmacological matching to recombinanthomomeric channels is difficult. Measurement of ion channel current defines the functional plasma membranechannel pool; this is a crucial advantage over biochemical approaches (Western blot or PCR). This pharmacologicalprofile method should be applied with caution. The antagonists (or gating modifier no.) listed on the left are appliedcumulatively in order to inhibit the conductances indicated in the middle. Resolution of ambiguous pharmacologyis achieved by secondary experiments using the additional pharmacology indicated by the vertical blue arrows.Additional constraints and confirmation of Kv identity is obtained from the time course and current–voltagerelations of the current measured under voltage clamp, as summarized on the right. ∗Low concentrations of TEAwill also block Kv1.1 homomeric channels. ∗∗ 4-aminopyridine will block many Kv1 and Kv3 subunits at micromolarconcentrations and most Kvs at millimolar concentrations; If Kv4 (A-current) is present it may be effectively removedby induction of inactivation, without need of pharmacological agents. #Stromatoxin is a gating modifer, shiftingthe activation voltage to more positive potentials, rather than an antagonist.



equate to azimuth sound location (McAlpine et al. 2001;Grothe, 2003). IPSPs from the MNTB need to be asprecisely timed as the EPSPs, i.e. for phase-locked firingbeyond 1 kHz during the sound (Smith et al. 1998; Paolini

et al. 2001; Kopp-Scheinpflug et al. 2003; Tollin & Yin,2005) and ensure that inhibition is linearly representedso that firing is restricted to only one AP per cycle of thesound wave.

Figure 3. Contribution of MNTB-inhibition to auditory brainstem processingInset, a sketch of a coronal brain section at the level of the superior olivary complex. Sound-evoked activity fromthe contralateral ear arrives as AP trains in the ventral cochlear nucleus (VCN) which sends excitatory projectionsto the MNTB (red lines, +). MNTB neurons give inhibitory projections (blue lines, −) to the medial superior olive(MSO), the lateral superior olive (LSO), the superior paraolivary nucleus (SPN) and the nuclei of the lateral lemniscus(NLL). All four target nuclei receive direct excitatory inputs from the VCN (not shown). A, excitation to each MNTBneuron is mediated via a calyx of Held synapse (red line) whose activity can be detected in extracellular recordingsas a presynaptic AP preceding the postsynaptic AP (modified from Kopp-Scheinpflug et al. 2008b with permissionfrom Elsevier). B, MSO cells receive glycinergic IPSPs directly onto their somata. Without inhibition, the peak of theITD function lies within the physiologically relevant range of ITDs (yellow shaded area) and ITDs are encoded bya topographic map. Well-timed inhibition reduces the firing rate but also shifts the peak ITD function out of thephysiological range. In this scenario the slope of the ITD function can be used to encode ITDs via a rate code. Tonic(non-phase-locked) inhibition causes a reduction in firing rate but without the respective shift of the ITD function(figure modified from Pecka et al. 2008 with permission from the Society for Neuroscience). C, LSO cells respondto ipsilateral sound stimulation with increased firing rates. Increasing the strength of the inhibitory input leadsto successive reductions in firing rate. Dot raster plots resemble the activity at about 20, 50 and 80% reductionof firing rate. The inhibition needs to be rather strong to suppress the onset component (figure modified fromPark et al. 1997, with permission from the American Physiological Society). D, SPN cells receive a sustainedinhibitory input which effectively suppresses AP firing during sound stimulation. The termination of a soundis then highlighted by an AP offset response (unpublished data; see also Kadner et al. 2006). E, NLL neuronsreceive low-frequency inhibition (blue area and histogram below), in addition to a higher-frequency excitatoryCF-stimulation (red area and histogram below). When both stimuli are presented at 0 ms delay, the excitatory CFresponse is suppressed (overlaying blue and red areas) and a post-inhibitory rebound is observed (red part of thehistogram; figure modified from Peterson et al. 2009 with permission from the American Physiological Society).



(2) The LSO projection. High-frequency sounds(≥2 kHz) are located by comparison of interauraldifferences in sound intensity (IID) caused by reflectionfrom and refraction around the head. The LSO integratesEPSPs originating from the ipsilateral VCN and IPSPsfrom the MNTB via the contralateral VCN at a matchingsound frequency (Tsuchitani, 1997). Firing evoked by theipsilateral EPSP is suppressed by increased sound intensityat the contralateral (inhibitory) ear, with the firing ratebeing described by the IID function (Fig. 3C). The dotraster plots in Fig. 3C show that complete suppression ofthe onset APs is achieved by intense inhibition. Changesin either timing (of the IPSP or EPSP) or intensity, cansubstitute for the other parameter (Pollak, 1988). IIDs aregenerally integrated over short time periods (Tollin, 2003)which makes onset precision essential. Over these periodsthe MNTB inhibitory input must have a large firing rangeso as to encode inherently small intensity differences.

(3) The SPN projection. The mammalian auditorybrainstem also contains circuits adapted for gap andsound duration detection which define the end of asound (Kadner et al. 2006; Kadner & Berrebi, 2008).This contributes to vocal communication and speech inhumans (see review Walton, 2010). The SPN receivespredominantly contralateral excitatory input from thecochlear nucleus (Schofield, 1995) and a strong, tonotopicinhibitory input from the MNTB (Banks & Smith, 1992).AP firing is suppressed during the sound by MNTB IPSPsand when the sound ceases, the SPN is released fromthe inhibition and generates rebound APs as an ‘offsetresponse’ (Fig. 3D). This offset response is blocked byglycinergic antagonists (Kulesza et al. 2007). The MNTBmust convey sustained inhibition for the whole durationof the stimulus and have a rapid termination, so as not tosuppress the offset firing in the SPN.

(4) The NLL projection. The NLL analyzes complexsounds by temporal segregation of spectrally integratedinputs and is suggested to be involved in echo suppression(Pecka et al. 2007). Inhibition has two roles. First, theexcitatory response to a CF stimulus is suppressed bysimultaneous delivery of a low-frequency (LF) inhibitorystimulus, while a change in timing between the twosounds abolishes the suppressive effect (Peterson et al.2009; Fig. 3E). Second, a powerful onset inhibition inthe NLL delays the CF excitatory response (Nayagamet al. 2005) and undermines the precise mutual timingbetween LF and CF tones. This onset inhibition has broadfrequency tuning, so it may arise from convergence ofMNTB neurons with a range of CFs. The glycinergicinhibition may also act directly at the excitatory inputformed by another calyx synapse which originates frombroadly tuned octopus cells in the VCN (Vater & Feng,

1990). In the MNTB, glycine can be excitatory at the CF,while maintaining its classical inhibitory role at spectrallydistant frequencies (Kopp-Scheinpflug et al. 2008a); thisparadox may involve presynaptic modulation as reportedfor the calyceal synapse (Turecek & Trussell, 2001). Similarmechanisms underlying glycinergic transmission havebeen proposed in the NLL (Kutscher & Covey, 2009). Thus,a precisely timed strong inhibition from the MNTB wouldbe required by the NLL.

Understanding the requirement of the target nucleiallows us to frame ideas concerning the properties to whichthe output of MNTB neurons must conform. Precisetiming with low jitter and no aberrant firing is requiredfor ITD discrimination in the MSO. For IID processingin the LSO, the MNTB requires a large firing range toencode the range of sound intensities. Offset encodingis probably the least demanding in terms of precisionbut requires sustained firing for long time periods. TheNLL projection must also have a precisely timed onset,although our understanding of its overall role here is stillto be elucidated. For each of these discrete circuits theMNTB is providing IPSPs that must integrate with EPSPsarising from a shorter synaptic chain, and therefore thetransmission delay to the MNTB must be brief, and theAPs well timed and able to sustain high frequencies withminimal aberrant firing.

Physiology of the MNTB, a key role for K+ channels

To fulfil its role in the circuitry of the auditorybrainstem, the MNTB needs to have the following intrinsicproperties: fidelity in terms of input vs. output, abilityto generate high and sustained firing rates, and APtiming accuracy. A further refinement is rapid synaptictransmission from its presynaptic input to minimizelatency jitter. A physical constraint on fast transmissionimposed by all neuronal membranes is the exponential(capacitive) rather than instantaneous charging of themembrane. Each MNTB neuron receives a large excitatorysynapse called the calyx of Held (Held, 1893; Morest,1968), which originates from the globular bushy cellsof the contralateral cochlear nucleus (Spirou et al. 1990;Kuwabara et al. 1991; Smith et al. 1991). In response to asingle presynaptic stimulus, this giant synapse generates anexcitatory postsynaptic conductance (EPSG) of between100 and 300 nS (Johnston et al. 2009), which effectivelysupercharges the MNTB membrane, rapidly bringing itto firing threshold. Although the exuberant size of thepresynaptic input confers minimal time delays betweenthe presynaptic and postsynaptic APs, the initial currentmagnitude and short term depression during repetitivestimulation generate other more subtle problems forinformation transmission.



Fidelity: preservation of the timing and pattern of APtrains across the MNTB relay

The large calyceal input generates an EPSC which canbe 30-fold larger than that required to trigger one APand so should trigger multiple APs in response to asingle presynaptic AP. This would undermine processingin the LSO, where the inhibition should scale linearlywith intensity, and the MSO, where aberrant APs wouldbe mis-timed and poorly synchronized with the phase.However, the MNTB never fires more than a single APfor each presynaptic input. This remarkable one-to-onefidelity is due to low voltage-activated channels formedfrom Kv1.1 and Kv1.2 subunits (Brew & Forsythe, 1995;Dodson et al. 2002). In the MNTB Kv1 channels beginto activate from around –67 mV and are half-activatedby ∼−40 mV (Fig. 4Ac and d; Brew & Forsythe, 1995).Their crucial role was demonstrated by application ofDTx-I, which results in multiple postsynaptic APs beinggenerated in response to a single EPSC (Fig. 4Aa). Kv1channels also contribute to AP firing threshold and APamplitude (Dodson et al. 2002; Klug & Trussell, 2006).

The powerful control on AP firing exerted by a relativelysmall Kv1 conductance is made possible by their specialsubcellular location in the axon initial segment (AIS) ofthe MNTB axon (Fig. 4Ab) (Dodson et al. 2002; Johnstonet al. 2008a; Clark et al. 2009) along with voltage-gatedsodium channels (Kuba et al. 2006; Kuba & Ohmori,2009). A simple NEURON model of the MNTB (shown inFig. 4Ae) reinforces this, showing that passive propertiesalone permit spread of large and sustained depolarizationinto the axon. With somatic Kv1 channels, depolarizationis largely shunted; however, when placed in the AIS, theKv1 shunt is even more effective. Kv1 channels located inthe AIS will act as a high-pass filter permitting only largefast rising voltage signals to trigger APs.

Although they are not present in the MNTB (Johnstonet al. 2008a), Kv7 channels (M-current) are present ininitial segments of some neurons (Brown & Passmore,2009), where they serve analogous roles in suppressingfiring. In mice, ether-a-go-go-related gene (ERG) channelsserve a complementary role with Kv1 (Hardman &Forsythe, 2009). Since ERG channels show increasedcurrent when the extracellular [K+] is raised, ERGchannels may exert most influence during periods ofhigh-frequency firing when extracellular K+ accumulatesand EK is depolarized.

High firing rate

Brief APs allow a neuron/axon to sustain higher firingrates. The MNTB has extremely brief APs with half-widthsof ∼400 μs due to the rapid kinetics of Kv3 channels(Fig. 4Bd and e) (Brew & Forsythe, 1995; Wang et al. 1998a;Rudy & McBain, 2001). The function of Kv3 channels

is conceptually simple: the positive activation voltageof Kv3 channels limits their activation to voltages onlyachieved during the AP (Fig. 4Bb and e), yet their rapidkinetics ensure they are deactivating during the fallingphase of the AP (Fig. 4Bb), but can contribute to a fastafter-hyperpolarization. The contribution of Kv3 channelsto brief APs is demonstrated by the AP broadeningfollowing application of 1–3 mM TEA (Fig. 4Ba) (Brew& Forsythe, 1995; Wang et al. 1998a). Short APs willminimize Nav inactivation and thus assist maintainedfiring (Fig. 4Bf ) while the fast Kv3 deactivation willavoid extending refractory periods. However, all activeKv conductances (Fig. 1B) will contribute to the APamplitude and time course, including Kv1 (see above) andKv2. Indeed the large synaptic conductance will influenceAP waveform (Johnston et al. 2009) and during the peak ofan overshooting AP (while V m is positive to EEPSC) couldassist AP repolarization.

Kv3 channels are located in the somatic membraneand axons, including nodes of Ranvier (Devaux et al.2003) in the trapezoid body (Fig. 4Bc); this will ensurerapid discharging of the postsynaptic membrane aftereach EPSP. Kv3 channels are also present at the calyx ofHeld terminal, but are located on the non-release faceof the terminal and postsynaptically between the fingersof the calyx (Elezgarai et al. 2003). This exclusion fromthe synaptic cleft will minimize K+ efflux into the smallvolume of the cleft which would otherwise cause localdepolarization or depletion of intracellular [K+] from finestructures (Wang et al. 1998b).

Maintained firing

Although the large AMPA receptor (AMPAR)-mediatedEPSC decays extremely rapidly, a slow component remains(Barnes-Davies & Forsythe, 1995; Taschenberger & vonGersdorff, 2000; Johnston et al. 2009) and summates withrepetitive stimulation (>50 Hz), resulting in APs beingtriggered during sustained depolarization (Taschenberger& von Gersdorff, 2000). Depolarization during theinter-spike period reduces the pool of available sodiumchannels and can lead to AP failure (Jung et al. 1997;Johnston et al. 2008a). In the MNTB Kv2.2 causesinter-spike potential to be more negative and consequentlysodium channels recover more quickly from inactivation(Fig. 4Ca). Kv2.2 is a delayed rectifier with relativelyslow kinetics and a positive activation range (Fig. 4Ccand d), so intuitively it will be less activated duringsingle short APs. However, their slow deactivation rateallows maintained activation during the inter-spike inter-val and also results in cumulative activation duringhigh-frequency firing. Like Kv1 channels, the Kv2.2channels are localized at the AIS (Fig. 4Cb, the location of



Figure 4. K+ channel physiology of the MNTBA, Kv1 channels ensure one-to-one fidelity. Aa, application of DTx results in multiple action potentials onthe tail of the EPSP generated in response to each presynaptic stimulus (Brew & Forsythe, 1995). Ab, Kv1immunohistochemistry shows that Kv1 channels are located in the axon initial segment (Dodson et al. 2002);



sodium channels) where they provide a hyperpolarizingdrive whose gain is determined by firing frequency(Fig. 4Ce). Similar AIS targeting of Kv2.1 and Kv2.2 isobserved in hippocampal and cortical neurones (Hwanget al. 1993; Sarmiere et al. 2008).

Accurate timing and low jitter

Preservation of timing information requires precisionand minimal jitter (variance) in the response ofthe postsynaptic cell to the presynaptic input. Asalready mentioned the large synaptic input ensures arapid response, but the MNTB also implements othermechanisms to further reduce jitter. Kv1 channels havebeen shown to lower the time constant of the MNTB,promoting more precise firing (Fig. 4Da); blocking Kv1channels in vitro resulted in increased jitter with repetitivestimulation (Gittelman & Tempel, 2006; Klug & Trussell,2006). Increased levels of jitter have also been observed inin vivo recordings from Kv1.1 KO mice (Kopp-Scheinpfluget al. 2003), though this was largely achieved upstream ofthe MNTB, probably in the presynaptic axons of the calyx.

The large Kv3 conductance facilitates high frequencyfiring; however, it also introduces timing errors atmoderate frequencies (Fig. 4Dd). This could be due toincreases in the relative refractory period (Macica et al.2003; Song et al. 2005), which may introduce a shunt atthe cell body, preventing the AIS from charging rapidly (seeFig. 4Ae). The magnitude of the Kv3 current in the MNTBis dynamically regulated by its phosphorylation state(Fig. 4Db and c). Under basal conditions Kv3 is partially

scale bar is 20 μm. Ac and d, DTx blocks a LVA K+ current with a V0.5 of −43 mV (Brew & Forsythe, 1995; Dodsonet al. 2002 with permission, SfN.). Ae, a simple NEURON model (Hines & Carnevale, 2001) of the MNTB with a1.8 nA current injection at the soma. The voltage at the soma and at the end of the AIS is plotted in blue and green,respectively, and shown assuming passive properties (left) Kv1 channels located at the soma (middle) and with Kv1channels in the AIS (right). Note that with Kv1 channels in the AIS the voltage in the soma differs from the AIS,which explains the apparent lowering of action potential threshold seen with DTx application (Dodson et al. 2002).B, Kv3 channels ensure high firing rates. Ba, blocking Kv3 channels with TEA slows action potential repolarization.Bb, Kv3 current activates with the action potential peaking at the start of repolarization (reproduced from Klug& Trussell, 2006 with permission from the American Physiological Society). Bc, Kv3 immunohistochemistry showsthese channels in the MNTB cell body and in the axon (arrow indicates nodes of Ranvier); scale bar is 40 μm. Bdand e, 1 mM TEA blocks a high voltage-activated K+ current with a V0.5 of ∼10 mV. Bf , the Kv3 mediated rapidrepolarization is essential for high firing rates (Wang et al. 1998). C, Kv2 channels enable sustained firing. Ca, ina single compartment NEURON model, removing Kv2 results in a depolarized inter-spike potential and reducedavailability of Nav channels causing shorter APs. Cb, Kv2 channels are located in the AIS along with Kv1 channels;scale bar is 20 μm. Cc and d, Kv2 channels mediate a slow activating high voltage-activated K+ current. Ce, Kv2current is activated in a frequency-dependent manner and remains active during the inter-spike potential (Johnstonet al. 2008a). D, decreased jitter with Kv1 channels and regulation of Kv3 channels. Da, Kv1 channels decrease themembrane time constant and improve the timing of MNTB neurons during repetitive stimulation (reproduced fromGittelman & Tempel, 2006 with permission from the American Phsyiological Society). Db, Kv3 phosphorylationstate is regulated by activity; scale bar is 100 μm. Dc, dephosphorylation occurs in loud auditory environments orwith high frequency stimulation and increases Kv3 current magnitude. Dd, large Kv3 magnitudes prolong firingbut introduce jitter (Song et al. 2005 reproduced with permission, Nature Neuroscience); under quiet conditionsKv3 is phosphorylated and timing errors are minimized.

inactive, but with high frequency synaptic stimulation(e.g. 600 Hz for 20 s) or moderate sound stimulation, Kv3becomes dephosphorylated and active (Song et al. 2005),which promotes higher frequency firing.

Discussion

The auditory brainstem is an example of a system inwhich ion channel function can be addressed at themolecular, cellular and physiological level. Whole-cellpatch recordings permit identification of voltage-gatedpotassium currents from MNTB neurons. A commontheme in ion channel regulation of excitability is preciselocalization in specific neuronal compartments; many Kvchannels are located in the axon initial segment (Kv1,Kv2, Kv3) while Kv3, but neither Kv1 nor Kv2, channelswere observed in excised somatic membrane patches(Johnston et al. 2008a). A generalized overview of Kvchannel localization is provided in Fig. 5. Kv1 channelslimit multiple firing following activation of the giantsynapse and Kv3 channels repolarize the action potential.Recent evidence shows that Kv2.2 complements Kv3 andis of increasing relevance during inter-spike intervals instimulus trains. A similar role has been proposed forsodium-activated K+ (IKNa) channels (Yang et al. 2007)although IKNa may not contribute under all experimentalconditions (Johnston et al. 2008a). Other potassiumconductances mediated by HCN, ERG and Kv4 channels(Johnston et al. 2008b) are present, but with relativelysmall conductances and further work is required to under-stand their various specific and complementary roles inMNTB function.



Potassium currents are crucial for MNTB neurons tomaintain high firing rates, avoiding aberrant firing, andto permit sustained longer periods of firing. The physio-logical roles of ion channels in AP firing are often probedby current injection through the recording pipette ratherthan synaptic stimulation. Step current injection generatesonly a single initial AP in an MNTB neuron and doesnot produce physiological AP waveforms (Johnston et al.2009). The physiological input is a train of EPSPs, eachgenerating a single postsynaptic AP at its peak, but asinput frequencies approach refactory period intervals, solatency fluctuations and AP failures become inevitableas the synaptic conductance depresses (Hermann et al.2007; Hennig et al. 2008). MNTB cells fire at much higherrates for stimulus onset than for later times in the train,as seen in the phasic–tonic (primary-like post-stimulustime histogram) responses in vivo (Smith et al. 1998).In brain slices, MNTB cells can attain ‘instantaneous’high firing rates up to 800 Hz (Taschenberger & vonGersdorff, 2000), which requires the high safety factorof the calyx for postsynaptic AP generation especiallyat stimulus onsets (Kopp-Scheinpflug et al. 2008a).However, during maintained (>30 s to minutes) stimulior background spontaneous activity (Hermann et al.2007), failures in synaptic transmission start to occur,EPSPs drop below threshold and the MNTB firing ratesdecline. The calyx of Held–MNTB synapse has often

been described as maintaining a ‘one-to-one’ input/outputfidelity; this is true at low stimulus frequencies, whereKv1 channels suppress multiple firing to the giant calycealinput (Brew & Forsythe, 1995). But in terms of auditoryphysiology, the MNTB relay is best considered as a‘one-to-no-more-than-one’ transmission; i.e. failures interms of skipped cycles during high firing rates aretolerable (Macica et al. 2003; Kaczmarek et al. 2005; Songet al. 2005) from the computational viewpoint, since theAPs which do propagate are still well timed with respectto the sound wave (albeit at a lower overall firing rate).Failures of the EPSP to trigger APs in the target neuronhave been described in some studies (Guinan & Li, 1990;Kopp-Scheinpflug et al. 2002; Steinert et al. 2008; Lorteijeet al. 2009) although not all (McLaughlin et al. 2008).One issue is that the incoming AP train to the MNTB willalready have been conditioned and AP firing limited bytransmission through the VCN (Englitz et al. 2009) andthe cochlea. However, attainment of high transmissionrates must require similar adaptations at all levels of thepathway. Clearly activity-dependent modulation duringspontaneous firing (Hermann et al. 2007) and activationof nitrergic signalling induces transmission failures underphysiological conditions (Steinert et al. 2008).

Ligand-activated or inhibited K+ conductances arefamiliar concepts in terms of Kv7 (KCNQ), KIR3(KATP) and KCa1.1 (BK), but there is increasing evidence

Figure 5. Subcellular localization of voltage-gated K+ channelsSomatic Kv channels include Kv3 and ERG, but the major part of the conductance arises from channels in the axoninitial segment (AIS) which are dominated by Kv1, Kv2 and Kv3 channels (as well as voltage-gated sodium channels,Nav). The location of Kv4 on dendrites is implied from their absence in MNTB somatic membrane and evidencefrom other cell types. Nodes of Ranvier (NOR) contain Nav and Kv3, with Kv1 channels in the juxtaparanodal region,under the myelin sheath (Wang et al. 1993). The last NOR of the axon known as the heminode is particularlylarge for the Calyx (Leao et al. 2005) and contains Kv1 and Kv3 channels, with the majority of Kv3 being on thenon-release face of the synaptic terminal.



for activity-dependent modulation of voltage-gatedpotassium channels (e.g. Kv2.1, Chen et al. 2006; Park et al.2006) across many areas of the nervous system. ReducedKv1 currents (Leao et al. 2004) and Kv3 channel activity(von Hehn et al. 2004) are seen in hearing impaired ordeaf animals and during incubation with elevated [K+]o

(Liu & Kaczmarek, 1998; Tong et al. 2010). Future workwill focus on the signalling and homeostatic mechanismsby which synaptic input modulates Kv channel functionand the extent to which changes in Kv current aremediated by ion channel phosphorylation or trafficking.These approaches will provide important insights intothe mechanisms influencing ion channel activity duringauditory insult, deafness and disease. Recent evidencesuggests multiple levels of activity-dependent control inthe MNTB. Synaptic stimulation, lasting seconds andinvolving PKC (Macica et al. 2003; Desai et al. 2008)and the protein phosphatases PP1/PP2A, mediates ashort-term facilitation of Kv3 conductances through netdephosphorylation in response to moderate sound levels(Song et al. 2005; Strumbos et al. 2010). Stimulation ofthe calyceal input over tens of minutes causes activationof nitric oxide signalling and suppression of Kv3 currents(Steinert et al. 2008) and potentiation of other delayedrectifiers by cGMP/PKG-dependent mechanisms. Theseobservations highlight the concept that the excitatorysynaptic input can modulate the excitability of the targetneuron by direct changes in voltage-gated potassiumchannels. This supports the notion that the calyx ofHeld–MNTB synapse is not an inert secure relay, butrequires active feedback and feedforward control in orderto tune neuronal excitability to recent synaptic activity.

References

Aldrich RW (2001). Fifty years of inactivation. Nature 411,643–644.

Armstrong CM & Binstock L (1965). Anomalous rectificationin the squid giant axon injected with tetraethylammoniumchloride. J Gen Physiol 48, 859–872.

Banks MI & Smith PH (1992). Intracellular recordings fromneurobiotin-labelled cells in brain slices of the rat medialnucleus of the trapezoid body. J Neurosci 12, 2819–2837.

Barnes-Davies M & Forsythe ID (1995). Pre- and postsynapticglutamate receptors at a giant excitatory synapse in ratauditory brainstem slices. J Physiol 488, 387–406.

Brew HM & Forsythe ID (1995). Two voltage-dependent K+conductances with complementary functions in postsynapticintegration at a central auditory synapse. J Neurosci 15,8011–8022.

Brew HM, Gittelman JX, Silverstein RS, Hanks TD, Demas VP,Robinson LC, Robbins CA, McKee-Johnson J, Chiu SY,Messing A & Tempel BL (2007). Seizures and reduced lifespan in mice lacking the potassium channel subunit Kv1.2,but hypoexcitability and enlarged Kv1 currents in auditoryneurons. J Neurophysiol 98, 1501–1525.

Brew HM, Hallows JL & Tempel BL (2003). Hyperexcitabilityand reduced low threshold potassium currents in auditoryneurons of mice lacking the channel subunit Kv1.1. J Physiol548, 1–20.

Brown DA & Passmore GM (2009). Neural KCNQ (Kv7)channels. Br J Pharmacol 156, 1185–1195.

Chen X, Yuan LL, Zhao C, Birnbaum SG, Frick A, Jung WE,Schwarz TL, Sweatt JD & Johnston D (2006). Deletion ofKv4.2 gene eliminates dendritic A-type K+ current andenhances induction of long-term potentiation inhippocampal CA1 pyramidal neurons. J Neurosci 26,12143–12151.

Clark BD, Goldberg EM & Rudy B (2009). Electrogenic tuningof the axon initial segment. Neuroscientist 15,651–668.

Clay JR (2009). Determining K+ channel activation curvesfrom K+ channel currents often requires the Goldman-Hodgkin-Katz equation. Front Cell Neurosci 3, 20.

Coetzee WA, Amarillo Y, Chiu J, Chow A, Lau D, McCormackT, Moreno H, Nadal MS, Ozaita A, Pountney D, Saganich M,Vega-Saenz de Miera E & Rudy B (1999). Molecular diversityof K+ channels. Ann N Y Acad Sci 868,233–285.

Desai R, Kronengold J, Mei J, Forman SA & Kaczmarek LK(2008). Protein kinase C modulates inactivation of Kv3.3channels. J Biol Chem 283, 22283–22294.

Devaux J, Alcaraz G, Grinspan J, Bennett V, Joho R, Crest M &Scherer SS (2003). Kv3.1b is a novel component of CNSnodes. J Neurosci 23, 4509–4518.

Dodson PD, Barker MC & Forsythe ID (2002). Twoheteromeric Kv1 potassium channels differentially regulateaction potential firing. J Neurosci 22, 6953–6961.

Dodson PD & Forsythe ID (2004). Presynaptic K+ channels:electrifying regulators of synaptic terminal excitability.Trends Neurosci 27, 210–217.

Doyle DA, Morais Cabral J, Pfuetzner RA, Kuo A, Gulbis JM,Cohen SL, Chait BT & MacKinnon R (1998). The structureof the potassium channel: molecular basis of K+ conductionand selectivity. Science 280, 69–77.

Elezgarai I, Dıez J, Puente N, Azkue JJ, Benıtez R, Bilbao A,Knopfel T, Donate-Oliver F & Grandes P (2003). Subcellularlocalization of the voltage-dependent potassium channelKv3.1b in postnatal and adult rat medial nucleus of thetrapezoid body. Neuroscience 118, 889–898.

Englitz B, Tolnai S, Typlt M, Jost J & Rubsamen R (2009).Reliability of synaptic transmission at the synapses of Heldin vivo under acoustic stimulation. PLoS One 4,e7014.

Garden DL, Dodson PD, O’Donnell C, White MD & Nolan MF(2008). Tuning of synaptic integration in the medialentorhinal cortex to the organization of grid cell firing fields.Neuron 60, 875–889.

Gittelman JX & Tempel BL (2006). Kv1.1 containing channelsare critical for temporal precision during spike initiation. JNeurophysiol 96, 1203–1214.

Glendenning KK, Brunso-Bechthold JK, Thompson GC &Masterton RB (1981). Ascending auditory afferents to thenuclei of the lateral lemniscus. J Comp Neurol 197, 673–703.

Grothe B (2003). New roles for synaptic inhibition in soundlocalization. Nat Rev Neurosci 4, 540–550.



Guinan JJ Jr & Li RY (1990). Signal processing in brainstemauditory neurons which receive giant endings (calyces ofHeld) in the medial nucleus of the trapezoid body of the cat.Hear Res 49, 321–334.

Gutman GA, Chandy KG, Adelman JP, Aiyar J, Bayliss DA,Clapham DE, Covarriubias M, Desir GV, Furuichi K,Ganetzky B, Garcia ML, Grissmer S, Jan LY, Karschin A, KimD, Kuperschmidt S, Kurachi Y, Lazdunski M, Lesage F, LesterHA, McKinnon D, Nichols CG, O’Kelly I, Robbins J,Robertson GA, Rudy B, Sanguinetti M, Seino S, StuehmerW, Tamkun MM, Vandenberg CA, Wei A, Wulff H &Wymore RS (2003). International Union of Pharmacology.XLI. Compendium of voltage-gated ion channels: potassiumchannels. Pharmacol Rev 55, 583–586.

Hardman RM & Forsythe ID (2009). Ether-a-go-go-related geneK+ channels contribute to threshold excitability of mouseauditory brainstem neurons. J Physiol 587, 2487–2497.

Harvey AL & Robertson B (2004). Dendrotoxins:structure-activity relationships and effects on potassium ionchannels. Curr Med Chem 11, 3065–3072.

Hassfurth B, Magnusson AK, Grothe B & Koch U (2009).Sensory deprivation regulates the development of thehyperpolarization-activated current in auditory brainstemneurons. Eur J Neurosci 30, 1227–1238.

Held H (1893). Die zentrale Gehorleitung. In Archiv furAnatomie und Physiologie, ed. His W & Du Bois-Reymond E,pp. 201–380. Leipzig Verlag von Veit und Comp, Leipzig.

Hennig MH, Postlethwaite M, Forsythe ID & Graham BP(2008). Interactions between multiple sources of short-termplasticity during evoked and spontaneous activity at the ratcalyx of Held. J Physiol 586, 3129–3146.

Hermann J, Pecka M, von Gersdorff H, Grothe B & Klug A(2007). Synaptic transmission at the calyx of Held underin vivo like activity levels. J Neurophysiol 98, 807–820.

Hines ML & Carnevale NT (2001). NEURON: a tool forneuroscientists. Neuroscientist 7, 123–135.

Hodgkin AL & Huxley AF (1952). A quantitative description ofmembrane current and its application to conduction andexcitation in nerve. J Physiol 117, 500–544.

Hwang PM, Fotuhi M, Bredt DS, Cunningham AM & SnyderSH (1993). Contrasting immunohistochemical localizationsin rat brain of two novel K+ channels of the Shab subfamily.J Neurosci 13, 1569–1576.

Jeffress LA (1948). A place theory of sound localization. J CompPsychol 41, 35–39.

Johnston J, Griffin SJ, Baker C & Forsythe ID (2008b). Kv4(A-type) potassium currents in the mouse medial nucleus ofthe trapezoid body. Eur J Neurosci 27, 1391–1399.

Johnston J, Griffin SJ, Baker C, Skrzypiec A, Chernova T &Forsythe ID (2008a). Initial segment Kv2.2 channels mediatea slow delayed rectifier and maintain high frequency actionpotential firing in medial nucleus of the trapezoid bodyneurons. J Physiol 586, 3493–3509.

Johnston J, Postlethwaite M & Forsythe ID (2009). The impactof synaptic conductance on action potential waveform:evoking realistic action potentials with a simulated synapticconductance. J Neurosci Methods 183, 158–164.

Joris P & Yin TC (2007). A matter of time: internal delays inbinaural processing. Trends Neurosci 30, 70–78.

Jung HY, Mickus T, Spruston N (1997). Prolonged sodiumchannel inactivation contributes to dendritic actionpotential attenuation in hippocampal pyramidal neurons. JNeurosci 17, 6639–6646.

Kaczmarek LK, Bhattacharjee A, Desai R, Gan L, Song P, vonHehn CA, Whim MD & Yang B (2005). Regulation of thetiming of MNTB neurons by short-term and long-termmodulation of potassium channels. Hear Res 206, 133–145.

Kadner A & Berrebi AS (2008). Encoding of temporal featuresof auditory stimuli in the medial nucleus of the trapezoidbody and superior paraolivary nucleus of the rat.Neuroscience 151, 868–887.

Kadner A, Kulesza RJ Jr & Berrebi AS (2006). Neurons in themedial nucleus of the trapezoid body and superiorparaolivary nucleus of the rat may play a role in soundduration coding. J Neurophysiol 95, 1499–1508.

Kandler K, Clause A & Noh J (2009). Tonotopic reorganizationof developing auditory brainstem circuits. Nat Neurosci 12,711–717.

Klug A & Trussell LO (2006). Activation and deactivation ofvoltage-dependent K+ channels during synaptically drivenaction potentials in the MNTB. J Neurophysiol 96,1547–1555.

Kopp-Scheinpflug C, Lippe WR, Dorrscheidt GJ & RubsamenR (2002). The medial nucleus of the trapezoid body in thegerbil is more than a relay: comparison of pre- andpostsynaptic activity. J Assoc Res Otolaryngol 4, 1–23.

Kopp-Scheinpflug C, Fuchs K, Lippe WR, Tempel BL &Rubsamen R (2003). Decreased temporal precision ofauditory signalling in Kcna1-null mice: anelectrophysiological study in vivo. J Neurosci 23, 9199–9207.

Kopp-Scheinpflug C, Dehmel S, Tolani S, Dietz B, Milenkovic I& Rubsamen R (2008a). Glycine mediated changes of onsetreliability at a mammalian central synapse. Neuroscience 157,432–445.

Kopp-Scheinpflug C, Tolnai S, Malmierca MS & Rubsamen R(2008b). The medial nucleus of the trapezoid body:Comparative physiology. Neuroscience 154, 160–170.

Kuba H, Ishii TM & Ohmori H (2006). Axonal site of spikeinitiation enhances auditory coincidence detection. Nature444, 1069–1072.

Kuba H & Ohmori H (2009). Roles of axonal sodium channelsin precise auditory time coding at nucleus magnocellularis ofthe chick. J Physiol 587, 87–100.

Kulesza RJ Jr, Kadner A & Berrebi AS (2007). Distinct roles forglycine and GABA in shaping the response properties ofneurons in the superior paraolivary nucleus of the rat. JNeurophysiol 97, 1610–1620.

Kutscher A & Covey E (2009). Functional role of GABAergicand glycinergic inhibition in the intermediate nucleus of thelateral lemniscus of the big brown bat. J Neurophysiol 101,3135–3146.

Kuwabara N, DiCaprio RA & Zook JM (1991). Afferents to themedial nucleus of the trapezoid body and their collateralprojections. J Comp Neurol 314, 684–706.

Leao RN, Berntson A, Forsythe ID & Walmsley B (2004).Reduced low-voltage activated K+ conductances andenhanced central excitability in a congenitally deaf (dn/dn)mouse. J Physiol 559, 25–33.



Leao RM, Kushmerick C, Pinaud R, Renden R, Li GL,Taschenberger H, Spirou G, Levinson SR & von Gersdorff H(2005). Presynaptic Na+ channels: locus, development, andrecovery from inactivation at a high-fidelity synapse. JNeurosci 25, 3724–3738.

Liu SQ & Kaczmarek LK (1998). Depolarization selectivelyincreases the expression of the Kv3.1 potassium channel indeveloping inferior colliculus neurons. J Neurosci 18,8758–8769.

Lorteije JA, Rusu SI, Kushmerick C & Borst JG (2009).Reliability and precision of the mouse calyx of Held synapse.J Neurosci 29, 13770–13784.

Macica CM, von Hehn CA, Wang LY, Ho CS, Yokoyama S, JohoRH & Kaczmarek LK (2003). Modulation of the Kv3.1bpotassium channel isoform adjusts the fidelity of the firingpattern of auditory neurons. J Neurosci 23, 1133–1141.

MacKinnon R (2003). Potassium channels. FEBS Lett 555,62–65.

Maffie J & Rudy B (2008). Weighing the evidence for a ternaryprotein complex mediating A-type K+ currents in neurons. JPhysiol 586, 5609–5623.

Mathews PJ, Jercog PE, Rinzel J, Scott LL & Golding NL (2010).Control of submillisecond synaptic timing in binauralcoincidence detectors by Kv1 channels. Nat Neurosci 13,601–609.

McLaughlin M, Van Der Heijden M & Joris PX (2008). Howsecure is in vivo synaptic transmission at the calyx of Held? JNeurosci 28, 10206–10219.

McAlpine D, Jiang D & Palmer AR (2001). A neural code forlow-frequency sound localization in mammals. Nat Neurosci4, 396–401.

Morest DK (1968). The growth of synaptic endings in themammalian brain: a study of the calyces of the trapezoidbody. Z Anat Entwicklungsgesch 127, 201–220.

Nayagam DA, Clarey JC & Paolini AG (2005). Powerful onsetinhibition in the ventral nucleus of the lateral lemniscus. JNeurophysiol 94, 1651–1654.

Oertel D (1999). The role of timing in the brain stem auditorynuclei of vertebrates. Annu Rev Physiol 61, 497–519.

Oertel D, Shatadal S & Cao XJ (2008). In the ventral cochlearnucleus Kv1.1 and subunits of HCN1 are colocalized atsurfaces of neurons that have low-voltage-activated andhyperpolarization-activated conductances. Neuroscience 154,77–86.

Paolini AG, FitzGerald JV, Burkitt AN & Clark GM (2001).Temporal processing from the auditory nerve to the medialnucleus of the trapezoid body in the rat. Hear Res 159,101–116.

Park KS, Mohapatra DP, Misonou H & Trimmer JS (2006).Graded regulation of the Kv2.1 potassium channel byvariable phosphorylation. Science 313, 976–979.

Park TJ, Monsivais P & Pollak GD (1997). Processing ofinteraural intensity differences in the LSO: role of interauralthreshold differences. J Neurophysiol 77,2863–2878.

Pecka M, Brand A, Behrend O & Grothe B (2008). Interauraltime difference processing in the mammalian medialsuperior olive: the role of glycinergic inhibition. J Neurosci28, 6914–6925.

Pecka M, Zahn TP, Saunier-Rebori B, Siveke I, Felmy F,Wiegrebe L, Klug A, Pollak GD & Grothe B (2007). Inhibitingthe inhibition: a neuronal network for sound localization inreverberant environments. J Neurosci 27, 1782–1790.

Peterson DC, Nataraj K & Wenstrup J (2009). Glycinergicinhibition creates a form of auditory spectral integration innuclei of the lateral lemniscus. J Neurophysiol 102,1004–1016.

Pollak GD (1988). Time is traded for intensity in the bat’sauditory system. Hear Res 36, 107–124.

Robertson B (1997). The real life of voltage-gated K+ channels:more than model behaviour. Trends Pharmacol Sci 18,474–483.

Rudy B & McBain CJ (2001). Kv3 channels: voltage-gated K+channels designed for high-frequency repetitive firing.Trends Neurosci 24, 517–526.

Sarmiere PD, Weigle CM & Tamkun MM (2008). The Kv2.1 K+channel targets to the axon initial segment of hippocampaland cortical neurons in culture and in situ. BMC Neurosci 9,112–127.

Schneggenburger R & Forsythe ID (2006). The calyx of Held.Cell Tissue Res 326, 311–337.

Schofield BR (1995). Projections from the cochlear nucleus tothe superior paraolivary nucleus in guinea pigs. J CompNeurol 360, 135–149.

Smith AJ, Owens S & Forsythe ID (2000). Characterisation ofinhibitory and excitatory postsynaptic currents of the ratmedial superior olive. J Physiol 529, 681–698.

Smith PH, Joris PX, Carney LH & Yin TC (1991). Projectionsof physiologically characterized globular bushy cell axonsfrom the cochlear nucleus of the cat. J Comp Neurol 304,387–407.

Smith PH, Joris PX & Yin TC (1998). Anatomy and physiologyof principal cells of the medial nucleus of the trapezoid body(MNTB) of the cat. J Neurophysiol 79, 3127–3142.

Song P, Yang Y, Barnes-Davies M, Bhattacharjee A, HamannM, Forsythe ID, Oliver DL & Kaczmarek LK (2005). Acousticenvironment determines phosphorylation state of the Kv3.1potassium channel in auditory neurons. Nat Neurosci 8,1335–1342.

Spirou GA, Brownell WE & Zidanic M (1990). Recordingsfrom cat trapezoid body and HRP labelling of globular bushycell axons. J Neurophysiol 63, 1169–1190.

Stanfield PR (1983). Tetraethylammonium ions and thepotassium permeability of excitable cells. Rev PhysiolBiochem Pharmacol 97, 1–67.

Steinert JR, Kopp-Scheinpflug C, Baker C, Challiss RA, MistryR, Haustein MD, Griffin SJ, Tong H, Graham BP & ForsytheID (2008). Nitric oxide is a volume transmitter regulatingpostsynaptic excitability at a glutamatergic synapse. Neuron60, 642–656.

Strumbos JG, Polley DB & Kaczmarek LK (2010). Specific andrapid effects of acoustic stimulation on the tonotopicdistribution of Kv3.1b potassium channels in the adult rat.Neuroscience 167, 567–572.

Taschenberger H & von Gersdorff H (2000). Fine-tuning anauditory synapse for speed and fidelity: developmentalchanges in presynaptic waveform, EPSC kinetics, andsynaptic plasticity. J Neurosci 20, 9162–9173.



Tollin DJ (2003). The lateral superior olive: a functional role insound source localization. Neuroscientist 9, 127–143.

Tollin DJ & Yin TC (2005). Interaural phase and level differencesensitivity in low-frequency neurons in the lateral superiorolive. J Neurosci 25, 10648–10657.

Tong H, Steinert JR, Robinson SW, Chernova T, Read DJ,Oliver DL & Forsythe ID (2010). Regulation of Kv channelexpression and neuronal excitability in rat medial nucleus ofthe trapezoid body maintained in organotypic culture. JPhysiol 588, 1451–1468.

Trussell LO (1999). Synaptic mechanisms for coding timing inauditory neurons. Annu Rev Physiol 61, 477–496.

Tsuchitani C (1997). Input from the medial nucleus oftrapezoid body to an interaural level detector. Hear Res 105,211–224.

Turecek R & Trussell LO (2001). Presynaptic glycine receptorsenhance transmitter release at a mammalian central synapse.Nature 411, 587–590.

Vater M & Feng AS (1990). Functional organization ofascending and descending connections of the cochlearnucleus of horseshoe bats. J Comp Neurol 292, 373–395.

von Hehn CA, Bhattacharjee A & Kaczmarek LK (2004). Lossof Kv3.1 tonotopicity and alterations in cAMP responseelement-binding protein signaling in central auditoryneurons of hearing impaired mice. J Neurosci 24, 1936–1940.

Wang H, Kunkel DD, Martin TM, Schwartzkroin PA & TempelBL (1993). Heteromultimeric K+ channels in terminal andjuxtaparanodal regions of neurons. Nature 365, 75–79.

Wang L, Gan L, Forsythe ID & Kaczmarek LK (1998a).Contribution of the Kv3.1 potassium channel tohigh-frequency firing in mouse auditory neurones. J Physiol509, 183–194.

Wang LY, Gan L, Perney TM, Schwartz I & Kaczmarek LK(1998b). Activation of Kv3.1 channels in neuronal spine-likestructures may induce local potassium ion depletion. ProcNatl Acad Sci U S A 95, 1882–1887.

Walton JP (2010). Timing is everything: Temporal processingdeficits in the aged auditory brainstem. Hear Res 264, 63–69.

Williams SR & Mitchell SJ (2008). Direct measurement ofsomatic voltage clamp errors in central neurons. NatNeurosci 11, 790–798.

Yang B, Desai R & Kaczmarek LK (2007). Slack and Slick KNa

channels regulate the accuracy of timing of auditoryneurons. J Neurosci 27, 2617–2627.

Yavuzoglu A, Schofield BR & Wenstrup JJ (2010). Substrates ofauditory frequency integration in a nucleus of the laterallemniscus. Neuroscience (in press).

Yellen G (2002). The voltage-gated potassium channels andtheir relatives. Nature 419, 35–42.

Zhou Y, Carney LH & Colburn HS (2005). A model forinteraural time difference sensitivity in the medial superiorolive: interaction of excitatory and inhibitory synapticinputs, channel dynamics, and cellular morphology. JNeurosci 25, 3046–3058.

Acknowledgements

Thanks to Martine Hamann and Joern Steinert for commentson the manuscript. We gratefully acknowledge funding from theMedical Research Council, UK.


symposium review: going native: voltage-gated potassium channels controlling neuronal excitability

Documents